JADE1

JADE1 is a PHD zinc-finger scaffold protein that operates at the interface of histone acetylation and Wnt signaling (PMID:18684714, PMID:18806787). As an essential co-factor of the HBO1 histone acetyltransferase complex, its N-terminal domain physically bridges HBO1 to its histone H3-H4 substrate and increases HBO1 catalytic efficiency ~5-fold in vitro, with its PHD fingers required for acetyltransferase stimulation but not for HBO1 binding (PMID:18684714, PMID:29382722); this complex is required for DNA synthesis and chromatin recruitment of the replication factor Mcm7 (PMID:23159946). JADE1 directs HBO1 activity in a sequence-specific manner, preferentially partnering with Oct4 bound at palindromic MORE DNA elements to drive H3K9 acetylation (PMID:41489900). Independently, JADE1 acts as an E3 ubiquitin ligase that ubiquitylates both phosphorylated and non-phosphorylated β-catenin, destabilizing wild-type β-catenin to suppress canonical Wnt signaling and linking the tumor suppressor pVHL to Wnt inhibition (PMID:18806787). JADE1 abundance and activity are set by direct partners: pVHL stabilizes JADE1 via its PHD-extended module, and renal-cancer-associated VHL mutations fail to stabilize it (PMID:12169691, PMID:14973063); the ciliary protein NPHP4 stabilizes and promotes nuclear translocation of JADE1 (PMID:22654112); polycystin-1 stabilizes JADE1 while its cytoplasmic tail promotes Siah-1-mediated JADE1 ubiquitination (PMID:23001567); and CK1α phosphorylation at a conserved SLS motif attenuates JADE1's Wnt-inhibitory activity (PMID:25100726). JADE1 also binds and inhibits AKT1 kinase, and its overexpression promotes apoptosis and suppresses renal cancer cell growth (PMID:16046545, PMID:23824745). Its chromatin association is cell-cycle-regulated, with Aurora A-dependent phosphorylation driving dissociation from chromatin at mitosis and re-association in telophase paralleling global H4 acetylation (PMID:24739512).

1. 2002 High

   Establishing JADE1 as a direct VHL-interacting partner whose stability is controlled by pVHL revealed a new VHL function and placed JADE1 in renal cancer biology.

   Evidence Yeast two-hybrid, reciprocal co-IP and metabolic labeling across cell lines

   PMID:12169691

   Open questions at the time

   • Did not define the molecular function of JADE1 itself
   • Mechanism of pVHL-mediated half-life extension unresolved
2. 2004 High

   Domain mapping showed VHL stabilization requires the JADE1 PHD module and that renal-cancer VHL mutants selectively fail to stabilize JADE1, tying JADE1 stabilization to tumor-suppressor function.

   Evidence Co-IP and metabolic labeling with VHL domain deletions and disease mutants

   PMID:14973063

   Open questions at the time

   • Did not establish how loss of JADE1 stabilization contributes to tumorigenesis
3. 2004 Medium

   First evidence of JADE1 as a transcriptional co-activator linked to histone acetylation, implicating its PHD fingers and a HAT partner.

   Evidence Gal4 reporter assays, acetyl-histone western blots, co-IP with TIP60, PHD deletions

   PMID:15502158

   Open questions at the time

   • TIP60 association reported here was superseded by HBO1 as the principal partner
   • No genomic targets defined
4. 2005 Medium

   Functional readout connected JADE1 to apoptosis and tumor suppression in renal cancer cells, motivating its mechanistic role downstream of VHL.

   Evidence Overexpression/antisense in renal cancer lines, apoptosis and colony assays, nude mouse xenografts

   PMID:16046545

   Open questions at the time

   • Molecular pathway linking JADE1 to Bcl-2 loss not defined
   • Single-lab phenotype
5. 2008 High

   Identification of JADE1 as an essential HBO1 HAT co-factor defined its core biochemical activity in promoting histone H4 acetylation.

   Evidence Co-expression, siRNA, in vitro HAT assay on reconstituted oligonucleosomes, PHD mutants

   PMID:18684714

   Open questions at the time

   • Structural basis of substrate bridging not yet resolved
   • Genomic distribution of HBO1-JADE1 acetylation unknown
6. 2008 High

   Discovery that JADE1 is an E3 ligase for β-catenin established the mechanism by which pVHL suppresses Wnt signaling through JADE1.

   Evidence Co-IP, ubiquitylation assays, siRNA, Wnt reporter assays

   PMID:18806787

   Open questions at the time

   • The catalytic determinants of JADE1 ligase activity not mapped
   • How a PHD scaffold also acts catalytically as an E3 unclear
7. 2012 Medium

   NPHP4 and polycystin-1 were shown to control JADE1 localization and stability, embedding JADE1 in ciliary and cystic-kidney signaling.

   Evidence Co-IP, colocalization at cilia transition zone, stability and ubiquitination assays, ADPKD mutants, zebrafish epistasis

   PMID:22654112 PMID:23001567

   Open questions at the time

   • Whether ciliary regulation of JADE1 feeds back to HAT activity unknown
   • Single-lab co-IP evidence
8. 2012 Medium

   The JADE1S-HBO1 complex was shown to be required for proliferation and DNA replication and to track kidney injury and regeneration.

   Evidence siRNA, DNA synthesis assays, Mcm7 ChIP, mouse ischemia-reperfusion model

   PMID:23159946

   Open questions at the time

   • Direct mechanism linking JADE1 to Mcm7 chromatin loading not established
   • Isoform-specific roles incompletely separated
9. 2013 Medium

   JADE1 was shown to bind and inhibit AKT1, extending its tumor-suppressive role to a kinase-inhibitory function downstream of pVHL.

   Evidence Kinase arrays, co-IP, overexpression/silencing, AKT domain-binding mapping

   PMID:23824745

   Open questions at the time

   • Structural basis of AKT inhibition unresolved
   • Single-lab evidence
10. 2014 Medium

    CK1α phosphorylation at the SLS motif was identified as a switch attenuating JADE1's Wnt-inhibitory activity, and Aurora A-dependent phosphorylation was shown to drive cell-cycle chromatin shuttling.

    Evidence In vitro kinase assays, SLS mutagenesis, Xenopus axis assay; fractionation, MS phosphosite mapping, Aurora A inhibitor, mouse kidney imaging

    PMID:24739512 PMID:25100726

    Open questions at the time

    • How phosphorylation integrates with E3 versus HAT functions unclear
    • Direct kinase responsible for each mitotic phosphosite not fully assigned
11. 2018 High

    Reconstitution defined JADE1 as the structural bridge linking HBO1 to histone H3-H4, mechanistically explaining its ~5-fold stimulation of HAT activity.

    Evidence In vitro reconstitution with recombinant proteins, HAT kinetics, deletion mapping in vitro and in vivo

    PMID:29382722

    Open questions at the time

    • High-resolution structure of the bridged complex not provided
    • Determinants of substrate specificity not defined
12. 2021 Medium

    JADE1 was linked to tauopathy, associating with 4R tau aggregates and modulating tau-induced neurotoxicity.

    Evidence Co-IP from human PART brain, immunohistochemistry, Drosophila rno knockdown with toxicity assays

    PMID:34719765

    Open questions at the time

    • Whether HAT or E3 activity mediates the tau interaction unknown
    • Single study, mechanism of toxicity modulation unclear
13. 2025 High

    Structural and genomic analysis showed JADE1-HBO1 is directed by Oct4 at palindromic MORE elements to drive site-specific H3K9 acetylation, defining a sequence-specific targeting mechanism for the complex.

    Evidence Co-IP, ChIP-seq, in vitro HAT assays on nucleosomes, knockdown, cryo-EM

    PMID:41489900

    Open questions at the time

    • How Oct4 recruitment relates to JADE1's E3 and proliferative roles unknown
    • Generality beyond Oct4-MORE sites not established

• How JADE1's two distinct biochemical activities — HBO1 co-factor scaffolding and β-catenin E3 ubiquitin ligase — are coordinated within a single protein, and how its many regulatory inputs integrate to switch between them, remains unresolved.
• No unified structural/biochemical model reconciling scaffold and ligase functions
• Catalytic mechanism of the E3 activity unmapped
• Interplay between mitotic shuttling, Wnt regulation, and HAT targeting unclear